Project summary Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis. The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms, and NRF2 has therefore emerged as a promising molecular target for the pharmacological prevention of human pathologies resulting from exposure to environmental toxicants including solar UV light. Pharmacological modulation of NRF2 has now attracted considerable attention as a novel approach to skin photoprotection supported by our own studies on NRF2 activation in cultured human skin cells and reconstructed epidermal skin models. The apocarotenoid bixin, an FDA-approved natural food colorant (referred to as 'annatto') originates from the seeds of the achiote tree native to tropical America, consumed since pre-Columbian times. Bixin is the only FDA approved, molecularly defined food pigment that displays potent NRF2-directed activity. Based on our published prototype data, the research pursued in this R03 research proposal will for the first time examine efficacy of bixin-based dietary activation of cutaneous NRF2 for acute skin photoprotection and suppression of chronic solar radiation-induced photocarcinogenesis. First, we will test feasibility of skin protection against acute damage (sunburn) from solar UV exposure in SKH-1 mice (Nrf2+/+ versus Nrf2-/-) by dietary supplementation using bixin (aim #1). Next, we will test feasibility of NRF2-dependent dietary suppression of solar UV-induced skin carcinogenesis using bixin supplementation in an established photocarcinogenesis model (Nrf2+/+ versus Nrf2-/- SKH-1 mice) (aim #2). Taken together, the proposed experimentation will generate crucial prototype data facilitating translational clinical research that substantiates the skin photoprotective and cancer-suppressive benefits provided by dietary consumption of this key food factor originating from the Americas.